Search Results (2,008)

Background/Aims: While pathogenic germline variants play a critical role in pediatric cancer susceptibility, traditional clinical genetics primarily focuses on single-gene interpretations. Transitioning to a systems-level analysis of inherited variation can uncover shared biological vulnerabilities, informing genetic counseling, surveillance, and targeted therapeutics. This study aims to implement an unsupervised machine learning framework to identify and characterize Germline Mutation Signatures (GMS) across diverse pediatric malignancies, elucidating latent genomic patterns that reveal shared oncogenic mechanisms. Methods: We analyzed germline whole-exome and whole-genome sequencing (WES/WGS) data from a retrospective cohort of 420 pediatric cancer patients and matched non-cancer controls. Variants were deeply annotated to capture multi-dimensional features, including predicted pathogenicity, splice-site disruption, regulatory impact, population frequency, and sequence context. To enable robust modeling, we integrated an augmented feature set encompassing evolutionary constraint, loss-of-function intolerance, and compositionally normalized substitution spectra. These high-dimensional annotations were processed using a deep autoencoder for non-linear representation learning, followed by Gaussian Mixture Modeling (GMM) of the latent space. Results: The framework delineated 13 signatures (GMS1–GMS13), yielding an optimal Davies–Bouldin index of 1.051. These signatures map to fundamental biological processes, including DNA repair deficiencies, transcription-coupled damage, replication stress, and aberrant RNA regulation. Crucially, these GMSs transcend traditional tissue-of-origin classifications, manifesting across multiple distinct cancer types. This observation indicates convergent germline etiologies and suggests potential shared susceptibilities to pathway-directed therapies. Conclusions: The discovery of these cross-cancer signatures provides a scalable, biologically interpretable framework for decoding inherited pediatric cancer risk. While the therapeutic mapping networks identified are currently exploratory and serve as a hypothesis-generating foundation, this deep learning-driven paradigm establishes a robust basis for stratified precision medicine. Pending prospective clinical validation, this approach holds significant translational potential to move beyond single-gene paradigms toward unified, systems-level precision oncology strategies. Full article

Cardiovascular disease and cancer remain the leading causes of death worldwide. Although numerous cancer therapies have improved survival rates, they also increase the risk of cardiomyopathy, heart failure, and arrhythmias. These cardiovascular complications can limit treatment options and adversely affect the long-term quality of life of cancer survivors. Ca_V1.3, an L-type calcium channel encoded by CACNA1D, emerges as a central molecular mediator linking cardiovascular disease and cancer. It regulates calcium entry into cardiomyocytes and contributes to sinoatrial pacemaking and atrioventricular conduction. It also contributes to proliferation, migration, and therapy resistance in several cancers. Chemotherapy-induced oxidative stress, inflammatory signaling, hypoxia, and transcriptional changes can modulate the expression, gating, splicing, and trafficking of Ca_V1.3 channels. All these changes destabilize diastolic depolarization and impair conduction, thereby promoting arrhythmias in cancer patients. This review focuses on Ca_V1.3 biology in cardio-oncology, along with the mechanisms of chemotherapy-induced cardiotoxicity. It outlines the role of Ca_V1.3 as a key mediator linking cancer therapies to subsequent nodal dysfunction and increased arrhythmia susceptibility. It also expands on how patient-specific induced pluripotent stem cell-derived cardiomyocytes can model Ca_V1.3 dysregulation as well as support the development of targeted therapies. We propose that Ca_V1.3 represents a mechanistic bridge linking cancer therapy, calcium signaling, and cardiac electrophysiology, and that elucidating its pathophysiology may guide the design of targeted strategies in cardio-oncology. Full article

Dietary factors, including the consumption of isoflavones-rich foods of plant origin, may contribute to the reduced incidence of prostate cancer. Isoflavones, natural phytoestrogens often found in legumes, can modulate estrogen and androgen receptor signaling. This study aimed to evaluate the biological potential of isoflavone-rich extracts obtained from twelve species from the Fabaceae family, targeting prostate cancer cell viability, proliferation, inflammatory markers, prostate-specific antigen secretion, and 5α-reductase activity. The tested extracts showed moderate cytotoxic activity against prostate cancer cell lines, apart from highly susceptible PC3 cells, and only weak toxicity to normal prostate epithelial cells. Significant antiproliferative activity was observed, especially for Cytisus scoparius, Ononis arvensis, and Genista tinctoria, while most extracts reduced prostate-specific antigen (PSA) secretion in normal prostate cells. Furthermore, the extracts showed anti-inflammatory properties by reducing the pro-inflammatory cytokine interleukin 6 (IL-6) and improving cytokine balance indices. Multivariate analyses revealed correlations between total isoflavone content and antiproliferative activity. Full article

Non-thermal millimeter-wave (MMW) irradiation represents a promising non-invasive strategy for cancer therapy, yet its effects in physiologically relevant 3D systems remain poorly defined. Here, we evaluated the biological impact of MMW exposure in 3D non-small-cell lung cancer (NSCLC) spheroids (NCI-H1299, A549) and normal WI-38 fibroblasts under active cooling to suppress bulk heating. We demonstrate that cellular responses are governed primarily by power density (PD), irradiation geometry, and genotype-dependent susceptibility. High-PD pyramidal horn (PH) irradiation (~4.9 mW/cm²) induced rapid apoptosis, metabolic collapse, and near-complete loss of clonogenic survival, whereas lower-PD waveguide (WG) irradiation (~0.6 mW/cm²) produced depth-limited, cumulative cytotoxicity. Surviving cancer cells exhibited robust senescence-associated growth arrest, particularly in p53-deficient NCI-H1299 cells, indicating a dual apoptotic–senescent anti-proliferative response. In contrast, WI-38 fibroblasts showed minimal apoptosis and only transient stress-associated senescence, confirming selective tumor vulnerability. Mechanistic modeling suggests that MMW energy couples to glycan-rich membrane domains, generating localized electromagnetic hotspots that trigger calcium influx, mitochondrial dysfunction, and depth-dependent apoptosis. These findings establish a mechanistic basis for selective, non-thermal MMW-induced cytotoxicity in 3D NSCLC models and support further preclinical development of MMW-based therapeutic strategies. Full article

Prostate cancer remains a major therapeutic challenge, particularly after progression to castration-resistant disease, where persistent androgen receptor signaling, metabolic adaptation, immune escape, and treatment resistance jointly limit clinical benefit. Regulated cell death (RCD) is increasingly recognized not only as an endpoint of tumor cell elimination but also as a dynamic regulator of prostate cancer progression, therapeutic vulnerability, and tumor–immune interactions. In this review, we propose an immunometabolic framework in which androgen receptor signaling, lipid and redox metabolic reprogramming, oxidative stress, and therapeutic pressure converge to shape the susceptibility of prostate cancer cells to distinct RCD modalities. We focus on autophagy and ferroptosis as two extensively studied and translationally relevant pathways, while also discussing emerging roles of necroptosis, pyroptosis, and cuproptosis. Particular attention is given to how RCD-associated signals, including damage-associated molecular patterns, inflammatory mediators, and lipid peroxidation products, may remodel the tumor immune microenvironment and influence the transition between immune-cold and immune-inflamed phenotypes. We further summarize RCD-targeted therapeutic strategies, including ferroptosis induction, autophagy inhibition, nanodrug delivery systems, rational combination therapy, and biomarker-guided patient stratification. Finally, we discuss key translational barriers, including context-dependent biological effects, limited clinical validation, tumor heterogeneity, adaptive resistance, and insufficient predictive biomarkers. By integrating cell death biology with metabolic reprogramming, immune remodeling, and therapeutic resistance, this review highlights RCD as a promising but context-dependent therapeutic vulnerability in advanced prostate cancer. Full article

The incidence of cancer in young adults has risen worldwide. Women comprise a disproportionate share of young-onset cases, among whom breast cancer predominates. This shift parallels globalization and urbanization, including the wider adoption of Western-pattern diets. Although hereditary syndromes explain a minority of cases, the secular rise underscores the impact of modifiable exposures, particularly diet. Prenatal life, neonatal life, childhood, adolescence, and early adulthood are critical periods during which dietary exposures may shape long-term mammary development. Mammary tissue undergoes rapid proliferation and differentiation during development, creating windows of heightened susceptibility to carcinogenic insults. However, most existing studies emphasize dietary exposures during a single developmental period; the entire span of critical developmental windows plays a formative role in shaping young-onset breast cancer (YoBC) risk, and the mechanisms underlying this life-course shaping remain insufficiently characterized. This review comprehensively synthesizes evidence on how nutrition across sensitive developmental windows shapes the risk of YoBC. We evaluate protective and adverse dietary factors within these stages and examine mechanistic pathways linking early-life nutrition to carcinogenesis, focusing on hormonal regulation, epigenetic programming, chronic inflammation, and the gut microbiome. A structured literature search was conducted in PubMed, Embase, and Web of Science for English-language articles published from 1990 through May 2026, supplemented by hand-searching of relevant reviews and key primary studies. By framing nutrition and breast cancer through a life-course lens, this review provides an integrated foundation for stage-specific prevention strategies and identifies priority directions for future research on early-life dietary determinants of YoBC. Full article

Prostate cancer (PrC) is one of the most common malignancies among men worldwide. However, the contribution of genetic variation in microRNA (miRNA) biogenesis pathway genes to PrC susceptibility remains poorly characterized in many ethnically diverse populations. We conducted a case–control study involving 532 PrC patients and 550 controls from the Volga-Ural region of Eurasia to evaluate the association of twenty-one single nucleotide polymorphisms (SNPs) with PrC risk using single-variant and polygenic approaches. Association analyses identified rs595055 in the AGO1 gene as significantly associated with PrC risk after correction for multiple testing. To evaluate the cumulative effect of genetic variation, weighted and unweighted polygenic risk scores (PRSs) were constructed. The weighted PRS was significantly associated with PrC risk (odds ratio per standard deviation increase = 1.63, 95% CI [1.43–1.85], P = 1.37 × 10⁻¹³), and demonstrated moderate discriminatory performance (AUC = 63.1%), outperforming the unweighted model. Individuals in the highest PRS quartile had approximately threefold higher odds of PrC than those in the lowest quartile. Combining the weighted PRS with prostate-specific antigen improved discrimination (AUC = 68.1%). These findings support the contribution of miRNA biogenesis pathway genes to PrC susceptibility and highlight the potential value of pathway-based polygenic risk stratification in understudied populations. Full article

Background/Objectives: Melanoma is a major and growing public health concern in Poland, with a five-year survival around 60–70%. While UV radiation and genetic susceptibility are well-known risk factors, lifestyle and environmental exposures may also contribute. This study examined how selected risk factors relate to one-year melanoma prevalence across Poland’s 16 voivodeships and assessed whether these factors can support short-term prediction. Methods: Annual melanoma prevalence for 2011–2021 was obtained from the Polish National Cancer Registry, and voivodeship-level estimates of metabolic risk factors, physical inactivity, alcohol consumption, smoking, high BMI, air pollution, water pollution and limited data on UV exposure were used to build a general estimating equations model. Model predictions for 2020–2021 were compared with observed data, and forecasts were generated through 2030. Results: Melanoma cases increased in every voivodeship between 2011 and 2021. Metabolic risk factors, high BMI, low physical activity and smoking were associated with higher melanoma prevalence. When other factors were considered, air pollution showed an inverse association, suggesting complex relationships that warrant further analysis. Forecasts indicated increasing prevalence in all of 16 voivodeships through 2030, although three regions showed large prediction errors for 2020–2021. A key limitation was the lack of sufficient UV exposure data. Conclusions: The findings support further evaluation of public health actions targeting the reduction of unhealthy lifestyle regarding diet, low physical activity, and smoking to help slow the projected rise in melanoma. Full article

Basonuclin 2 (BNC2) is a highly conserved cysteine–histidine (C2H2)-type zinc-finger nuclear regulatory protein characterized by three pairs of zinc-finger domains, a putative nuclear localization signal, a serine-rich region, broad tissue distribution, and remarkable transcript diversity generated through alternative promoter usage, alternative splicing, and polyadenylation. Increasing evidence from human genetics, animal models, functional genomics, and transcriptomic studies indicates that BNC2 links nuclear regulatory mechanisms to tissue-specific developmental and disease phenotypes. In the nervous system, BNC2-positive neuronal populations and BNC2-derived circular RNAs have been implicated in energy-balance circuits and neuroinflammatory regulation. In the skeletal system, BNC2 contributes to osteochondral development, periosteal stem-cell activation, chromatin remodeling, fracture repair, and genetic susceptibility to adolescent idiopathic scoliosis. BNC2 variants have also been associated with congenital lower urinary tract obstruction, whereas its expression and regulatory landscape are closely related to germ-cell development, epithelial ovarian cancer susceptibility, pigmentation traits, fibrosis, and several tumor contexts. Mechanistically, BNC2-associated phenotypes appear to involve cysteine–histidine zinc-finger-mediated transcriptional regulation, non-coding enhancer activity, epigenetic alterations, RNA-processing-associated nuclear functions, and chromatin-remodeling-dependent control of cell proliferation, differentiation, and stromal activation. This review integrates current evidence on the molecular architecture and regulatory functions of BNC2, critically discusses its context-dependent roles across development and disease, and highlights unresolved questions regarding isoform-specific activity, cell-type-specific regulation, downstream target networks, and clinical translation. A clearer understanding of these mechanisms may support the future evaluation of BNC2 as a biomarker, genetic susceptibility locus, molecular stratification factor, and potential therapeutic regulatory node. Full article

Background/Objectives: Microtubule-targeting agents represent a pillar of cancer chemotherapy; however, their clinical utility is constrained by significant toxicity, pharmacokinetic instability, and susceptibility to multidrug resistance transporters. This study aimed to explore the impact of replacing substituted phenyl rings with a naphthalene moiety in sulfonamide-based colchicine-site ligands, with the goal of identifying new antiproliferative candidates with improved profiles. Methods: We designed, synthesized, and evaluated a library of 35 naphthalene sulfonamides bearing varied aryl groups and sulfonamide nitrogen substituents. We assessed the antiproliferative activity against multiple cancer cell lines. Mechanistic studies, including fluorescence microscopy, cell cycle analysis, and cell death assays, were performed to evaluate the effect of these compounds on microtubule polymerization dynamics and cell fate. Molecular docking and in silico pharmacokinetic profiling were carried out to support the proposed binding mode at the colchicine site and to assess drug-likeness. Results: Exclusively, compounds bearing a trimethoxyphenyl group showed antiproliferative activity in the submicromolar range, thus identifying it as a structural requirement. The most potent compound (2) reached double-digit nanomolar IC₅₀ values (67–104 nM) across multiple cancer cell lines. Microscopy confirmed intracellular disruption of microtubule polymerization. Unlike colchicine, these compounds did not induce canonical mitotic arrest but instead triggered apoptotic cell death. In silico analyses supported binding at the colchicine site and revealed favorable predicted pharmacokinetic properties. Conclusions: The naphthalene sulfonamides described herein demonstrate potent antiproliferative activity through a distinct mechanism compared to colchicine, and their favorable in silico profiles position them as promising candidates for further development as antitumor agents. Full article

Critically ill obese patients with gynecological cancer represent a high-risk population with complex nutritional needs. Although excess adiposity may suggest adequate energy reserves, it often conceals sarcopenia, micronutrient deficiencies, and functional malnutrition, contributing to impaired wound healing, immune dysfunction, prolonged mechanical ventilation, increased susceptibility to infections, and adverse oncologic outcomes. Obesity-associated inflammation, insulin resistance, and tumor-driven catabolism further exacerbate metabolic stress and complicate nutritional management in the intensive care setting. Accurate nutritional assessment requires a multimodal approach incorporating body composition analysis, functional measures, and laboratory parameters, as conventional indices such as body mass index may underestimate nutritional risk. Nutritional support should be individualized and may include early enteral nutrition to preserve gut integrity, supplemental or total parenteral nutrition when gastrointestinal function is compromised, high-protein regimens, and targeted micronutrient replacement. Immunonutrition, including arginine, glutamine, omega-3 fatty acids, and nucleotides, has emerged as a promising strategy to modulate inflammation, enhance immune function, and support tissue repair. This narrative review summarizes current evidence regarding obesity-related metabolic dysfunction, nutritional assessment, enteral and parenteral nutrition, and immunonutrition in obese critically ill patients with gynecological cancer. It highlights the challenges associated with sarcopenic obesity and hidden malnutrition while providing a clinically relevant overview for intensivists, gynecologic oncologists, surgeons, and nutrition specialists. Early recognition of nutritional risk and implementation of individualized multimodal nutritional strategies may improve recovery and clinical outcomes. However, high-quality ICU-specific studies remain limited, and further prospective research is needed to establish evidence-based nutritional protocols and evaluate their impact on survival, treatment tolerance, and quality of life in this vulnerable population. Full article

Endocrine-disrupting chemicals (EDCs) are a heterogeneous group of exogenous compounds capable of interfering with hormonal homeostasis and endocrine-regulated physiological processes. Their widespread occurrence in food, water, air, consumer products and industrial materials has raised increasing concern regarding their contribution to chronic disease burden. This review synthesizes current evidence on the exposure characteristics, molecular mechanisms, health effects, and prevention strategies related to major EDC classes, including bisphenol A and phthalates, dioxins and polychlorinated biphenyls, per- and polyfluoroalkyl substances, pesticides, and brominated flame retardants. Evidence indicates that EDCs may act through receptor-mediated signaling, altered hormone synthesis and metabolism, oxidative stress, mitochondrial dysfunction, immune modulation, and epigenetic mechanisms, with effects that may vary according to dose, timing, sex, age, and developmental susceptibility. Reported health outcomes include metabolic and cardiovascular disorders, reproductive dysfunction, hormone-dependent cancers, thyroid disruption, immune dysregulation, and adverse developmental effects. Although complete avoidance is unrealistic, exposure reduction and risk mitigation can be achieved through coordinated individual, clinical, environmental, and regulatory interventions. A life-course approach is essential to limit the health burden associated with endocrine disruption. Full article

Background: Gastrointestinal (GI) cancers, particularly colorectal, gastric, and liver cancers, account for a major global burden of incidence and mortality and remain important targets for genetic susceptibility research. Long non-coding RNAs (lncRNAs) can regulate gene expression and are increasingly studied in carcinogenesis. Numerous case–control studies have investigated associations between lncRNA polymorphisms and cancer risk, but findings are inconsistent. This study systematically evaluated the association between lncRNA single nucleotide polymorphisms (SNPs) and GI cancer susceptibility. Methods: A systematic literature search from Embase, Medline, Scopus, and Web of Science databases identified 174 potentially extractable studies. Eligible studies were case–control or cross-sectional studies published up to 8 May 2026; case reports, reviews, and meta-analyses were excluded. After screening for identical cancer type, identical SNP, and sufficient statistical data, only variants supported by at least three independent case–control studies were eligible for meta-analysis. Seven SNPs across six lncRNAs, comprising 23 studies (15,131 cases and 20,969 controls), were selected. Because of the limited number of eligible studies, subgroup analyses could not be performed consistently. Odds ratios (ORs) with 95% confidence intervals (CIs) were assessed under allelic, dominant, and recessive genetic models using fixed- or random-effects models according to heterogeneity. Results: In the primary analyses restricted to homogenous Chinese populations, H19 rs3024270 was significantly associated with hepatocellular carcinoma under allelic (OR = 1.22, 95% CI: 1.05–1.42, p = 0.01) and dominant models (OR = 1.22, 95% CI: 1.03–1.45, p = 0.02). Exploratory analyses including mixed populations identified additional associations, with the strongest observed for MEG3 rs7158663 and colorectal cancer, showing significant risk elevation under allelic (OR = 1.42, 95% CI: 1.25–1.63, p < 0.00001), dominant (OR = 1.42, 95% CI: 1.20–1.68, p < 0.0001), and recessive models (OR = 1.98, 95% CI: 1.46–2.68, p < 0.0001). PRNCR1 rs16901946 showed a significant association with gastric cancer under the dominant model (OR = 1.20, 95% CI: 1.02–1.41, p = 0.03), while GAS5 rs145204276 demonstrated a recessive-model association with gastric cancer (OR = 1.30, 95% CI: 1.16–1.46, p < 0.0001). In contrast, GAS5 rs145204276 in colorectal cancer; H19 rs2839698 and MALAT1 rs619586 in hepatocellular carcinoma yielded heterogeneous or unstable pooled estimates. Findings should be interpreted cautiously due to the limited number of studies, heterogeneity, and potential publication bias. Conclusions: Among the primary analyses, H19 rs3024270 showed the most consistent association with HCC susceptibility. Exploratory analyses identified candidate variants, including MEG3 rs7158663, PRNCR1 rs16901946, and GAS5 rs145204276. Population-specific effects and study heterogeneity remain important limitations. PROSPERO registration number for this study: CRD42023389742. Full article

Background: Cervical cancer is among the most common cancers affecting women worldwide, with high morbidity and mortality in low- and middle-income countries. In Saudi Arabia, most cases are diagnosed at a late stage despite the availability of free HPV vaccination and screening. Objectives: To identify Saudi women’s perceptions of the HPV vaccine using the Health Belief Model, estimate willingness to receive the HPV vaccine and the factors influencing it, assess uptake of Pap smear and HPV vaccine, and define barriers to both practices. Methodology: A cross-sectional study of a convenience sample of 1334 Saudi women aged 16 to 65 years, from all regions of Saudi Arabia, was conducted. Data were collected via an online questionnaire that included sociodemographic characteristics, beliefs about the HPV vaccine based on the Health Belief Model, vaccine hesitancy, and HPV vaccine and Pap smear uptake. Data were analyzed using SPSS version 29. Results: Only 6% completed their vaccination series or received at least one dose; 37.3% planned to get vaccinated; and 56.7% stated they do not intend to get vaccinated. The main reasons for vaccine refusal were lack of trust (41.8%) and fear of side effects (32.3%). Only 21% had undergone Pap smear testing, with barriers including embarrassment and fear. Among the HBM constructs, perceived susceptibility, benefits, and barriers remained statistically significant predictors of HPV vaccination. Increased perceived susceptibility and benefits raise the likelihood of accepting the HPV vaccine, while higher perceived barriers lessen it. Vaccine hesitancy had a significant negative effect on willingness to receive the HPV vaccine (OR = 0.78, 95% CI 0.69–0.90, p < 0.01). Additionally, Pap smear uptake was an independent predictor of the intent to get the HPV vaccine (OR = 1.78, 95% CI 1.25–2.54, p < 0.01). The independent factors influencing HPV vaccine uptake were largely similar to those affecting the willingness to receive the vaccine, except for age, perceived benefits, and Pap smear uptake. Conclusions: There is a gap between Saudi women’s intention to get HPV vaccinated and actual vaccination. Women who saw a high risk of HPV-related cancer, believed in vaccine efficacy, had a Pap smear, and were open to vaccination were more likely to vaccinate. Hesitant women and those perceiving barriers were less likely to vaccinate or consider it. The main gaps for future campaigns are perceptions of HPV severity and cultural factors influencing decision-making. Emphasizing HPV as a cancer-related virus rather than a sexually transmitted infection can reduce barriers and highlight its severity. Full article

Testicular germ cell tumor (TGCT) is a common tumor type in young men. Family history of TGCT and its presence in twins support the involvement of inherited genetic factors. Germline exome sequencing was performed on monozygotic twins with TGCT and their parents. The twins presented compound heterozygous variants in PDE11A (rs776984134 and rs17400325) inherited from each parent. The rs776984134 variant disrupts the canonical splice acceptor site, leading to aberrant splicing and a frameshift predicted to affect protein structure. The rs17400325 missense variant, located in the catalytic domain, reduces hydrogen bonding capacity and may impair protein stability. Both variants map to a genomic region overlapping the antisense lncRNA PDE11A-AS1. In silico transcript-level analysis predicted multiple energetically favorable RNA–RNA interactions between PDE11A and PDE11A-AS1 transcripts, with rs17400325 located within predicted hybridization regions of several isoforms. These results suggest a potential impact on PDE11A–PDE11A-AS1 pairing and post-transcriptional regulation. Additional variants in MSH6 and CTU2 were also identified and may act as potential modifiers of disease susceptibility, consistent with a multigenic contribution to TGCT risk. These findings support a contributory role for the PDE11A locus in TGCT predisposition and underscore the biological relevance of overlapping sense–antisense genomic regions in hereditary cancer studies. Full article